Eph receptor tyrosine kinases (Ephs) belong to a large group of receptor tyrosine kinases (RTKs), kinases that phosphorylate proteins on tyrosine residues. Ephs and their membrane bound ephrin ligands (ephrins) control cell positioning and tissue organization (Poliakov, A., et al., Dev Cell 7:465-80 (2004)). In contrast to other receptor tyrosine kinases, Eph receptor activation does not only require ligand binding and dimerization but also involves preformed ligand oligomers. Thus, tyrosine phosphorylation of Eph receptors requires presentation of ephrin ligands in their clustered or membrane-attached forms (Davis et al., Science 266:816-819 (1994)). Functional and biochemical Eph responses occur at higher ligand oligomerization states (Stein et al., Genes Dev 12:667-678 (1998)).
Among other patterning functions, various Ephs and ephrins have been shown to play a role in vascular development. The de-regulated re-emergence of some ephrins and their receptors in adults also has been observed to contribute to tumor invasion, metastasis and neo-angiogenesis. For example, dominant-negative, soluble EphA2 or A3 proteins exhibit effects on ephrin-induced endothelial cell function in vitro, and tumor angiogenesis and progression in vivo (Nakamoto, et al., Microsc Res Tech 59:58-67 (2002); Brantley-Sieders, et al., Curr Pharm Des 10:3431-42 (2004); Brantley, et al. Oncogene 21:7011-26 (2002); Cheng, et al. Neoplasia 5:445-56 (2003). Dobrzanski, et al. Cancer Res 64:910-9 (2004)). Furthermore, Eph family members have been found to be over-expressed on tumor cells from a wide variety of human solid tumors (Brantley-Sieders, et al., Curr Pharm Des 10:3431-42 (2004); Marme, D. Ann Hematol 81 Suppl 2:S66 (2002); Booth, C. et al., Nat Med 8:1360-1 (2002)).
Epha3 has also been reported to be activated and overexpressed on CD34+ cells in chronic myeloid leukemia (CML) patients in the accelerated phase and blast crisis stage (Cilloni et al., American Society of Hematology, Abstract 1092, 2008 (available on line Nov. 14, 2008)). Cilloni et al. reported that when primary CML cells or EphA3-transfected normal cells were incubated with a specific monoclonal antibody, the antibody induced a significant reduction of proliferation in primary cells and transfected cells, reduced colony growth and induced changes to the adhesion properties. The antibody did not induce any significant changes in normal control cells or cells from CML patient in the chronic stage.
This invention is based, in part, on the discovery of new anti-EphA3 antibodies.